chr3-37001049-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The ENST00000458205.6(MLH1):c.-422G>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,440,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

MLH1
ENST00000458205.6 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 9.42

Publications

7 publications found

Variant links:

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

MLH1 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
Lynch syndrome 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
Muir-Torre syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
mismatch repair cancer syndrome 1
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
Lynch syndrome 1
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
ovarian cancer
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
malignant pancreatic neoplasm
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
breast cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

REVEL computational evidence supports a deleterious effect, 0.967

PP5

Variant 3-37001049-G-A is Pathogenic according to our data. Variant chr3-37001049-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 90138.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.302G>A	p.Gly101Asp	missense_variant	Exon 3 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.302G>A	p.Gly101Asp	missense_variant	Exon 3 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1440370

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

717924

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32976

American (AMR)

AF:

0.0000224

AC:

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26014

East Asian (EAS)

AF:

0.00

AC:

AN:

39500

South Asian (SAS)

AF:

0.00

AC:

AN:

85798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5716

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1092578

Other (OTH)

AF:

0.00

AC:

AN:

59720

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2

Pathogenic:1

Jul 12, 2023

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 23403630]. This variant is expected to disrupt protein structure [PMID: 26249686, Myriad internal data].

Lynch syndrome 1

Pathogenic:1

Mar 09, 2018

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance:Likely pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.968

not provided

Pathogenic:1

Feb 02, 2021

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: reduced protein expression and MMR repair activity compared to wild type (Ellison 2004, Hinrichsen 2013); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and/or family histories consistent with Lynch syndrome (Taylor 2003, Tournier 2008); This variant is associated with the following publications: (PMID: 19224586, 15475387, 23403630, 22290698, 25525159, 14635101, 18561205, 31784484)

Hereditary cancer-predisposing syndrome

Pathogenic:1

Jan 29, 2021

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G101D variant (also known as c.302G>A), located in coding exon 3 of the MLH1 gene, results from a G to A substitution at nucleotide position 302. The glycine at codon 101 is replaced by aspartic acid, an amino acid with similar properties. Two in vitro functional studies demonstrated reduced MMR function for p.G101D when compared to wild-type MLH1 in yeast (Ellison AR et al. Nucleic Acids Res. 2004 ; 32(18):5321-38; Hinrichsen I et al. Clin. Cancer Res. 2013 May; 19(9):2432-41). The Hinrichsen study also found decreased expression (10-20% relative expression) for this variant when compared to wild-type. Based on internal structural analysis, this variant is highly destabilizing and resides in a known motif within close proximity to known pathogenic variants (Wu H et al. Acta Crystallogr F Struct Biol Commun. 2015 Aug; 71(Pt 8):981-5; Hol WG et al. Nature. 1978 Jun; 273(5662):443-6). The p.G101D variant was also identified in a family meeting Bethesda guidelines (Taylor CF et al. Hum. Mutat. 2003 Dec; 22(6):428-33). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.

Eigen

Pathogenic

0.91

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.0

.;.

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.0

.;.

MutationAssessor

Benign

0.0

.;.

PhyloP100

9.4

PROVEAN

Benign

0.0

.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.

Sift4G

Pathogenic

0.0

.;.

Vest4

0.0

ClinPred

1.0

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Varity_R

0.99

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over